Statistically, every third European develops cancer in his lifetime. In Germany every year about 395,000 human beings develop cancer, about 195,000 thereof are women and 200,000 are men. Most of these cases develop at the age of over 60 years.
Solid tumors are still a big challenge of the clinical oncology. A significant improvement of the prognosis of individual tumor diseases can almost exclusively be reached by establishing new principles of therapy, integrated into multimodal concepts.
One of these new principles of therapy relates to the application of replicating viruses for the treatment of tumors. This approach is referred to as virotherapy or oncolysis. Numerous viruses have oncolytic properties with a preferred replication in different tumor cells in comparison to a reduced replication in healthy parenchyma cells. Currently, multiple virotherapeutic agents are subject of several clinical trials.
Viruses of the family of Paramyxoviridae are of particular interest. Important members of this family of enveloped viruses are the Newcastle disease virus which belongs to the genus of Avulavirus, the Measles virus which belongs to the genus of Morbilliviruses, and the Sendai virus belonging to the genus of the Respiroviruses. 
The genome of the Paramyxoviruses comprises a negative single-stranded RNA, i.e. an RNA molecule encoding genes or open reading frames (ORFs) in the anti-sense mode. In a Sendai virus the 3′-head region of the RNA genome is followed by the viral genes N (Nucleocapsid), P (Phospho), M (Matrix), F (Fusion), HN (Hemagglutinin-Neuraminidase) and L (Large), followed by the 5′-tail region.
The N, P, and L proteins are required for the expression of the genes encoded by the genomic RNA and for the autonomous replication of the RNA. The HN protein supports the infection of specific cell types. The so-called Matrix protein (M) is a structure protein in the virus particle which is associated with the membrane.
The F protein has a central function in the infection by inducing the cell membran fusion which is necessary for the initial infection and the virus expansion to the neighboring cells. It is synthesized in virus-infected cells as an inactive precursor F0 and anchored in the lipid envelope of the virus which originates from the plasma membrane of the host cell. F0 is cleaved into the active subunits F1 and F2 by the tryptase “Clara” which can be found in the respiratory tract of rats and mice and is secreted from the bronchial epithelium cells. F1 and F2 have the capability to fuse cell membranes, thereby initiating the infection of the host by the virus. Therefore, the cleavage of F0 is a decisive determinate for the infectiousness and pathogenity of the Sendai virus. The protease restriction is an important determinant by which the infection with the Sendai virus in mice is restricted to the respiratory tract and cannot result in a systemic infection.
Kinoh et al. (2004), Generation of a recombinant Sendai virus that is selectively activated and lyses human tumor cells expressing matrix metalloproteinses, Gene Ther. 11, p. 1137-1145, propose the use of a genetically modified Sendai virus for the treatment of tumor diseases. The principle of the genetic modification is the introduction of an artificial cleavage site into the viral F protein, which is recognized and can be cleaved by tumor-specific matrix metalloproteinases and, thereby, should enable a tumor-specific replication of the modified viruses. Furthermore, the known genetically modified Sendai virus comprises a deletion in the viral M protein resulting in an inhibition of the release of offspring viruses in such a way that an expansion of the virus is only possible by cell-to-cell contacts via fusion. This modified Sendai virus is also disclosed in EP 1 505 154.
Kinoh et al. (2009), Generation of optimized and urokinase-targeted oncolytic Sendai virus vectors applicable for various human malignancies, Gene Ther. 16, p. 392-403, reports a genetically modified Sendai virus having a truncation of amino acids in the viral F protein which should result in an increase of the fusion activity. Furthermore, the viral F protein comprises a so-called “Urokinase Type Plaminogen Activator (uPA) Sensitive Sequence” (SGRS, SEQ ID NO:35) by which a cleavage and activiation of F0 through tumor-specific proteases should extend the replication capacity of the viruses to a multitude of tumors.
Elankumaran et al. (2010), Type I Interferone sensitive recombinant Newcastle-Disease-Virus for oncolytic virotherapy, Journal of Virology, online publication, propose the use of recombinant Newcastle disease viruses (rNDV) as an anti-tumor agent which either comprise a mutation in the V protein and is referred to as “rBC-Edit”, or a mutation in the F protein and is referred to as “rLaSota V.F.”.
US 2009/0175826 reports using a recombinant Newcastle disease virus (rNDV) as an oncolytic agent, which comprises a transgene which should induce apoptosis in tumor cell lines.
The oncolytic viruses described in the art so far have not proven of value. A clinical application with a defined proof of effectiveness is still to be demonstrated. In particular, the oncolytic viruses so far used in the art have the disadvantage of also infecting and destroying non-tumor cells to an extended degree. On these grounds the oncolytic viruses used so far are unusable in a clinical application. In addition, it is not clear for which tumor diseases a good effect of individual virus systems can be reached. For this reason the oncolytic viruses used so far are not usable in clinical applications.